Anticoagulants in Atrial Fibrillationlecom.edu/.../2016/03/2016...Atrial-Fibrillation.pdf · 3/2/2016 3 Atrial Fibrillation Anticoagulation Introduction Atrial fibrillation (AF) prevalence

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Anticoagulants inAtrial Fibrillation

Starting and Stopping Them Safely

Anticoagulants inAtrial Fibrillation

Starting and Stopping Them Safely

Carmine D’Amico, D.O.

Atrial Fibrillation Anticoagulation

Overview

Learning objectives

Introduction

Basic concepts

Treatment strategy & options

Summary

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Learning objectives1. List the major considerations to be addressed in the

management of atrial fibrillation.

2. Determine which patients with atrial fibrillation are appropriate candidates for anticoagulation.

3. Compare and contrast the various oral anticoagulants currently available for stroke prevention in atrial fibrillation.

4. Describe the adjustments in dosage or choice of oral anticoagulant that may be necessary due to changes in patients’ renal or hepatic function.


Learning objectives (cont.)5. Explain the safest way to stop and restart the

various oral anticoagulants for procedures that carry considerable bleeding risk.

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Introduction

Atrial fibrillation (AF) prevalence

5.2 million persons in the United States afflicted with AF (2010 data)

Projected AF prevalence in the United States in 2030: 12.1 million

Increases with age 0.1% of adults younger than 55 years

> 9% of adults 80 years or older


Introduction (cont.)

Atrial fibrillation (AF) incidence

Increases with age:

< 0.1 % per year in people < 40 years old

> 1.5 % per year in women > 80 years old

> 2 % per year in men > 80 years old

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Introduction (cont.)

Definitions of AF

Paroxysmal

Persistent

Permanent

Nonvalvular

Lone


Cornerstones of AF Management

Control of symptoms

Rate Control Antithrombotic Therapy

Rhythm Control

Ther

apeu

tic

Goal

s

Control of symptoms

Treatment or prevention of

tachycardia-induced cardiomyopathy

Reduction in Hospitalizations

Reduction in hospitalizations

Prevention of thromboembolism

Minimization of bleeding risk

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Emerging 4th pillar in AF management:

Cornerstones of AF Management

AF Risk Factor Modification

Obesity Low cardiorespiratory fitness Obstructive sleep apnea Hypertension Hyperlipidemia Diabetes mellitus Coronary artery disease

Miller JD et al. J Am Coll Cardiol. 2015;66:2899-2906.


Basic Concepts

Antithrombotic therapy

Rationale

CVA risk AF = 5 x age-matched controls

AF = A. flutter

Paroxysmal = Persistent = Permanent

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Basic Concepts (cont.)

Antithrombotic drugs Interfere with thrombus formation

Include: Antiplatelet drugs

Interfere with platelet plug formation

Anticoagulant drugs Interfere with fibrin formation


Basic Concepts (cont.) Thrombus composition varies with the site of

thrombus formation

Thrombi that form in arteries (high flow conditions) Platelets predominate

Relatively little fibrin

“White thrombi”

Thrombi that form in veins (slow flow conditions) Rich in fibrin and trapped red blood cells

Relatively few platelets

“Red thrombi”

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Strategy for Antithrombotic Selection


Treatment Strategy / Options (cont.)

Antithrombotic therapy (cont.)

Antithrombotic strategy must be individualizedbased on risk stratification

For nonvalvular AF, the CHADS2 scoring system and, more recently, the CHA2DS2–VAScscoring system is a useful method for estimating stroke risk in AF patients.

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Antithrombotic strategy must be individualizedbased on risk stratification (cont.)

These scoring systems, along with the HAS-BLED bleeding risk scoring system, may be used to guide antithrombotic therapy.

CHADS2 Risk Stratification Scheme

Risk Factors Score

C Congestive heart failure 1

H Hypertension 1

A Age 75 years 1

D Diabetes mellitus 1

S2 History of stroke or transient ischemic attack 2

Rockson et al. J Am Coll Cardiol. 2004;43:929-935.


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CHADS2 Risk Stratification Scheme (cont.)

Score Recommended therapy

0 Aspirin (81 to 325 mg daily)

1Aspirin (81 to 325 mg daily)

or Warfarin (INR 2.0 – 3.0)

2 - 6 Warfarin (INR 2.0 – 3.0)

Rockson et al. J Am Coll Cardiol. 2004;43:929-935.


CHA2DS2–VASc Risk Stratification SchemeRisk Factors Score

C Congestive heart failure 1

H Hypertension 1

A2 Age 75 years 2

D Diabetes mellitus 1

S2 History of stroke or transient ischemic attack 2

V Vascular disease 1

A Age 65 - 74 years 1

Sc Sex category (female gender) 1

Lip et al. Chest. 2010;137:263-272.


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CHA2DS2–VASc Risk Stratification Scheme (cont.)

Score Recommended therapy

0 “It is reasonable to omit antithrombotic therapy.”

1**** “No antithrombotic therapy,

treatment with oral anticoagulant, or aspirin may be considered.”

> 2 “Oral anticoagulants recommended.”

January et al. J Am Coll Cardiol. 2014;64(21):2246-2280.


CHA2DS2–VASc Score of “1”

****Females with a CHA2DS2–VASc Score of “1” are probably truly low-risk for stroke (and may not require anticoagulation for nonvalvular AF), whereas males with a CHA2DS2–VASc Score of “1” are probably at higher risk for stroke (and thus probably should be anticoagulated).

Kovacs et al. J Am Coll Cardiol. 2015;65(13):1340-1360.


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Additional recommendations:

For lone AF (<60 y/o and no heart disease), ASA or no antithrombotic therapy is acceptable.

Regardless of CHA2DS2–VASc score, anticoagulation is recommended for patients with AF and:

Hypertrophic cardiomyopathy

Mitral stenosis

Mechanical and bioprosthetic valve prostheses

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“Risk factors” on previous slide include:

Atrial fibrillation

Previous thromboembolism

LV dysfunction

Hypercoagulable condition

Older-generation mechanical valve prosthesis

HAS-BLED Risk Stratification SchemeRisk Factors Score

H Hypertension 1

A Abnormal renal and/or liver function (1 point each) 1 or 2

S Stroke 1

B Bleeding predisposition 1

L Labile INR’s 1

E Elderly (Age > 65) 1

D Drugs and/or alcohol usage 1 or 2

Pisters et al. Chest. 2010;138:1093-1100.


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HAS-BLED Risk Stratification Scheme (cont.)Risk Factor Specifics Score

H Uncontrolled hypertension (systolic BP > 160 mmHg) 1

A Abn. renal function (dialysis, transplant, Cr > 2.6 mg/dL)

Abn. liver function (cirrhosis, bilirubin > 2 x NL, AST/ALT/AP > 3 x NL) 1 or 2

S Stroke history 1

B Prior major bleeding or predisposition to bleeding 1

L Unstable/high INR’s, time in therapeutic range < 60% 1

E Elderly (Age > 65) 1

D Drugs (medication usage predisposing to bleeding (antiplatelet

agents, NSAID’s))

and/or alcohol usage (> 8 drinks/week)

1 or 2



HAS-BLED Risk Stratification Scheme (cont.)



“In patients with a HAS-BLED score > 3, caution and regular review are recommended, as well as efforts to correct the potentially reversible risk factors for bleeding.”

“A high HAS-BLED score per se should not be used to exclude patients from oral anticoagulant therapy.”

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There’s an app for that!

Enter: “ACC Guideline Clinical Apps”

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Oral anticoagulants

Warfarin

Dabigatran

Rivaroxaban

Apixaban

Edoxaban



Oral anticoagulants (cont.)Warfarin (Coumadin®, Jantoven®) Inhibits formation of the reduced form of vitamin K

Long half-life (37 hours) Delayed onset of anticoagulation: 2-7 days

Variability in warfarin’s anticoagulant effect Dietary variations in vitamin K content

Many drug interactions

Requires monitoring of PT/INR


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Oral anticoagulants (cont.)Dabigatran (Pradaxa®)

Oral direct thrombin inhibitor At least as effective as warfarin (in reducing the risk of stroke and

systemic embolism in patients with nonvalvular atrial fibrillation), without increased bleeding risk

No monitoring of coagulation studies needed

No dietary restrictions

Minimal drug interactions



Oral anticoagulants (cont.)Dabigatran (cont.)

Dose reduction necessary in renal insufficiency

Antidote now available: idarucizumab (Praxabind®)


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Oral anticoagulants (cont.)Rivaroxaban (Xarelto®)

Oral factor Xa inhibitor

Does not bind to antithrombin III

Once daily dosing



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Oral anticoagulants (cont.)Apixaban (Eliquis®)



Twice daily dosing



Oral anticoagulants (cont.)Apixaban (cont.)

Dose reduction necessary in patients with at least two of the following:

Age > 80 years

Weight < 60 kg

Serum Cr > 1.5 mg/dL


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Oral anticoagulants (cont.)Edoxaban (Savaysa®)



Once daily dosing


Avoid use if CrCl > 95 ml/min.



Oral anticoagulants – memory aid:

Warfarin

Dabigatran

Rivaroxaban

Apixaban

Edoxaban


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Warfarin

Dabigatran

Rivaroxaban

Apixaban

Edoxaban




Warfarin

Dabigatran: Direct thrombin inhibitor

Rivaroxaban: Factor Xa inhibitor

Apixaban: Factor Xa inhibitor

Edoxaban: Factor Xa inhibitor


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Warfarin: Vitamin K antagonist

Dabigatran: Direct thrombin inhibitor

Rivaroxaban: Factor Xa inhibitor

Apixaban: Factor Xa inhibitor

Edoxaban: Factor Xa inhibitor


Treatment Strategy / Options (cont.) Temporary interruption of oral anticoagulant therapy

for invasive procedures:

For nonvalvular atrial fibrillation, short-term interruption of oral anticoagulant therapy is safe for most low-risk invasive procedures.

For patients at higher thromboembolic risk who are undergoing high risk procedures, “bridging” with a parenteral anticoagulant becomes a stronger consideration.


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for invasive procedures (cont.):

Warfarin Number of days warfarin must be withheld prior to procedure

depends on that individual’s usual maintenance dose

Check INR prior to procedure to assure subtherapeutic level

Dabigatran If CrCl > 50 ml/min, stop dabigatran at least 1-2 days prior to

procedure

If CrCl < 50 ml/min, stop dabigatran at least 3-5 days prior to procedure



for invasive procedures (cont.):

Apixaban For moderate-high-bleeding risk procedures, stop apixaban at least

48 hours prior to the procedure.

For low bleeding-risk procedures, stop apixaban at least 24 hours prior to the procedure.

Rivaroxaban & edoxaban Stop rivaroxaban and edoxaban at least 24 hours prior to the

procedure.


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Treatment Strategy / Options (cont.) Dosing considerations for oral anticoagulants in

nonvalvular atrial fibrillation:

Warfarin One (of two) oral anticoagulants that may be used in patients with

severe renal dysfunction or end-stage renal disease (which is the other?)

Caution in patients with moderate-to-severe hepatic impairment.

Dabigatran If CrCl > 30 ml/min, dose is 150 mg PO BID

If CrCl is 15-30 ml/min, dose is 75 mg PO BID

If CrCl < 15 ml/min, avoid use



nonvalvular atrial fibrillation (cont.):

Apixaban

Usual dose is 5 mg PO BID, unless the patient has at least two of the following (in which case the recommended dose is 2.5 mg PO BID):

Age > 80 years

Weight < 60 kg

Serum Cr > 1.5 mg/dL

Is the other of the two oral anticoagulants that may be used in patients with severe renal dysfunction or end-stage renal disease


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Apixaban (cont.)

“For nonvalvular AF patients with ESRD maintained on hemodialysis, the recommended dose is 5 mg PO BID”

Reduce dose to 2.5 mg PO BID if the patient has at least one of the following:

Age > 80 years

Weight < 60 kg




Rivaroxaban If CrCl > 50 ml/min, dose is 20 mg PO daily

If CrCl is 15-50 ml/min, dose is 15 mg PO daily

If CrCl < 15 ml/min, avoid use

Edoxaban If CrCl is 51-95 ml/min, dose is 60 mg PO daily

If CrCl is 15-50 ml/min, dose is 30 mg PO daily

If CrCl > 95 ml/min, avoid use


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Special circumstance worth noting…

After coronary revascularization, in patients with nonvalvular AF and a CHA2DS2–VASc score > 1, current consensus is that “it may be reasonable to use clopidogrel concurrently with oral anticoagulants but without aspirin.”


Cardiovascular Case for questions 1 & 2

Use the following case for the next two questions:

A 46-year-old female presents for preoperative evaluation prior to elective total abdominal hysterectomy. Her medical history is significant for endometriosis, hypertension, and paroxysmal atrial fibrillation. An echocardiogram performed last month revealed normal left ventricular systolic function, mild tricuspid regurgitation, trace mitral regurgitation, and no significant structural abnormalities. Her medications include warfarin 2 mg PO daily and atenolol 25 mg PO BID. Her INR is 2.8. The remainder of her lab work (CBC and CMP) is within normal limits. Physical examination reveals: blood pressure 126/82 mmHg, pulse 80 bpm, and respirations 12 per min. There is no jugular venous distension, lungs are clear to auscultation bilaterally (no crackles or wheezes), cardiac rhythm is regular and there is no S3, S4, murmur, or rub. There is no peripheral edema.

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Cardiovascular Case 1

Question 1

Which of the following is the most appropriate recommendation regarding anticoagulation prior to surgery?

A. Discontinue warfarin now, as anticoagulation is not indicated in this patient.

B. Discontinue warfarin four days prior to scheduled surgery. Check the INR daily. When the INR is < 2, begin enoxaparin 1 mg/kg SQ BID and continue it until the morning of surgery.

C. Discontinue warfarin four days prior to scheduled surgery. Check the INR the morning of scheduled surgery. Proceed with surgery if the INR is < 2.

D. Continue warfarin through the day before scheduled surgery. Withhold warfarin on the morning of surgery and initiate a continuous intravenous infusion of unfractionated heparin, which may then be discontinued on call to the operating room.


Question 2

Provided that the surgery was uneventful, which of the following is the most appropriate recommendation regarding anticoagulation postoperatively?

A. Do not resume anticoagulation postoperatively, as it is not indicated in this patient.

B. Resume warfarin as soon as the surgeon feels that the patient is at a low risk for bleeding. Discharge the patient when the INR is > 2. C. Begin enoxaparin 1 mg/kg SQ BID and resume warfarin 2 mg PO daily as soon as the surgeon feels that the patient is at a low risk for bleeding. Check the INR daily. Discontinue enoxaparin and discharge the patient when the INR is > 2.

D. Begin enoxaparin 1 mg/kg SQ BID and resume warfarin 2 mg PO daily as soon as the surgeon feels that the patient is at a low risk for bleeding. Check the INR daily until the INR is > 2. Discontinue enoxaparin after 10 doses regardless of INR.

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Cardiovascular Case for questions 3 & 4

Use the following case for the next two questions: A 66-year-old male presents for preoperative evaluation prior to elective total right knee arthroplasty. His medical history is significant for DJD, type II diabetes mellitus, and paroxysmal atrial fibrillation. An echocardiogram performed three months ago revealed mild left ventricular systolic dysfunction (LVEF 45%), mild mitral regurgitation, trace tricuspid regurgitation, and mild thickening of the aortic valve without stenosis. His medications include rivaroxaban 20 mg PO daily, metformin 500 mg PO BID, sitagliptin 100 mg PO daily, metoprolol 25 mg PO BID, and acetaminophen 650 mg PO q 6 hrs. PRN pain. His preoperative lab work (including PT/INR, CBC, and CMP) are within normal limits. Physical examination reveals: Temperature 97.8 ̊ F, blood pressure 122/76 mmHg, pulse 68 bpm, and respirations 14 per min. There is no jugular venous distension, lungs are clear to auscultation bilaterally, cardiac rhythm is regular, a soft S4 is present, and there is no S3. A grade 2/6 pansystolic murmur is heard at the cardiac apex. Abdominal exam is unremarkable. With the exception of mild swelling of the right knee, there is no peripheral edema.


Question 3

Which of the following is the most appropriate recommendation regarding anticoagulation prior to surgery?

A. Discontinue rivaroxaban now, as anticoagulation is not indicated in this patient.

B. Discontinue rivaroxaban 48 hours prior to scheduled surgery. Begin enoxaparin 1 mg/kg SQ BID 24 hours after the last rivaroxaban dose. Discontinue enoxaparin on the morning of surgery.

C. Discontinue rivaroxaban 48 hours prior to scheduled surgery. Order a factor Xa inhibition assay on the morning of scheduled surgery. Proceed with surgery if the assay reveals subtherapeutic factor Xa inhibition.

D. Discontinue rivaroxaban 48 hours prior to scheduled surgery.

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Question 4

Provided that the surgery was uneventful, which of the following is the most appropriate recommendation regarding anticoagulation postoperatively?

A. Do not resume anticoagulation postoperatively, as it is not indicated in this patient.

B. Resume rivaroxaban 20 mg PO daily as soon as the surgeon feels that the patient is at a low risk for bleeding. Obtain a factor Xa inhibition assay daily after resuming rivaroxaban. Discharge the patient when the assay reveals therapeutic factor Xa inhibition. C. Begin enoxaparin 1 mg/kg SQ BID and resume rivaroxaban 20 mg PO daily as soon as the surgeon feels that the patient is at a low risk for bleeding. Discontinue enoxaparin after four days, as it takes five half-lives to achieve steady state with rivaroxaban.

D. Resume rivaroxaban 20 mg PO daily as soon as the surgeon feels that the patient is at a low risk for bleeding.


Case Presentation 3A 53-year-old male presents to his primary care physician’s office for a scheduled routine medical evaluation. He denies any symptoms or recent problems, and he states that he feels fine. His medical history is significant for coronary artery disease (having undergone implantation of a drug-eluting stent into the proximal LAD four months ago), hypertension, and hyperlipidemia. An echocardiogram performed one week after LAD stenting revealed normal left ventricular systolic function (LVEF 55%), mild mitral regurgitation, mild tricuspid regurgitation, moderate left atrial dilatation, and no other significant structural abnormalities. His current medications include aspirin 81 mg PO daily, clopidogrel 75 mg PO daily, atorvastatin 80 mg PO daily, metoprolol ER 100 mg PO daily, and ramipril 5 mg PO daily. Vital signs are: temperature 98.4 ̊F, blood pressure 124/78 mmHg, pulse 68 bpm, and respirations 12 per min. The remainder of the physical examination is unremarkable except for an irregularly irregular rhythm, and a grade 2/6 pansystolic murmur heard along the lower left sternal border and at the cardiac apex. A 12-lead electrocardiogram is obtained (see next slide).

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Question 5

Which of the following is the most appropriate recommendation regarding antithrombotic therapy for this patient? A. Continue aspirin and clopidogrel, without adding an oral anticoagulant.

B. Continue aspirin and clopidogrel, and begin oral anticoagulant therapy. C. Continue aspirin, discontinue clopidogrel, and begin oral anticoagulant therapy. D. Continue clopidogrel, discontinue aspirin, and begin oral anticoagulant therapy.

E. Discontinue both antiplatelet agents, and begin oral anticoagulant therapy.

Documents

Anticoagulants in Atrial Fibrillationlecom.edu/.../2016/03/2016...Atrial-Fibrillation.pdf · 3/2/2016 3 Atrial Fibrillation Anticoagulation Introduction Atrial fibrillation (AF) prevalence